| Resistin is an adipocyte-secreted hormone downregulated by the anti-diabetic thiazolidinedione class of insulin sensitizing drugs. Resistin has been implicated in contributing to obesity-related insulin resistance, a central component in the pathogenesis of type II diabetes. A unique cysteine-rich motif distinguishes resistin and defines a novel family of resistin-like molecules (RELMs).{09}Biochemical studies of resistin demonstrate it is secreted as a dimer from 3T3-L1 adipocytes. RELMβ is similarly secreted as a dimer, but RELMα is secreted as a monomer. The differential dimerization is a consequence of an N-terminal cysteine conserved in resistin and RELMβ, but not RELMα, and may have functional implications for the RELM family. To investigate the physiologic role of resistin gene targeting was used to generate resistin deficient (null) mice. Null mice are viable, healthy, fertile and grossly normal, with normal body weight, adiposity, ad libitum glucose and insulin levels. However, null mice have decreased fasting blood glucose and are protected from glucose intolerance following high fat diet-induced obesity. Hyperinsulinemic-euglycemic clamp studies showed that null mice have an 80% decrease in hepatic glucose production, a 4-fold decrease in hepatic G6Pase expression, and activation of AMP-activated protein kinase. Thus, mice lacking resistin have decreased gluconeogenic capacity and a greatly increased hepatic sensitivity to insulin action. Furthermore, the correlation between body weight and fasting glucose is reduced in null mice, suggesting that resistin may contribute to obesity related fasting hyperglycemia. These results suggest that resistin contributes to the regulation of glucose homeostasis. Together with other adipocyte-derived hormones, including adiponectin and leptin, resistin exemplifies the emerging role of adipose tissue as an endocrine organ. |
